The acute effects of the enkephalin analogue BW 942C in humans.

BW 942C hydrochloride is an enkephalin analogue that has exhibited a wide separation between antidiarrheal dosages and dosages inducing adverse effects in animals. This has likewise been the case in humans when administered orally. In this study, the safety and tolerance of single 0.5-mg doses of intravenous BW 942C compared with placebo were assessed in humans. Four healthy male volunteers received BW 942C, and two received placebo. The effects of BW 942C on serum growth hormone (GH), luteinizing hormone (LH), prolactin (PR), and follicle-stimulating hormone (FSH) were assessed in three of these volunteers. No significant changes were apparent in vital signs, in clinical chemistry, hematologic and urine studies following BW 942C administration. BW 942C did not appear to alter mood as assessed by two psychologic mood scales. Prolactin levels tended to increase in volunteers receiving BW 942C two hours postinfusion. Luteinizing hormone concentrations decreased slightly at two and six hours. No trends in FSH or GH could be identified. Pulmonary function testing did not reveal any significant changes in oximetry, spirometry, or plethysmography in any of the subjects. A marked decrease in CO2 responsiveness in two subjects may indicate that BW 942C has mild ventilatory depressant effects. Untoward effects experienced in volunteers receiving BW 942C included heaviness in the limbs, nasal stuffiness, mouth dryness, facial flushing, skin rash, and prickling sensations. These effects bear a striking similarity to those experienced after parenteral administration of other enkephalin analogues. Intravenous administration of BW 942C up to 0.5 mg appears safe from a laboratory, physiologic, and clinical perspective with unusual untoward effects that may preclude rational use of the drug by the parenteral route.

Private practice evaluation of the safety and efficacy of bupropion in depressed outpatients.

A multicenter uncontrolled 4-week trial of bupropion in depressed outpatients was conducted in the private practices of 25 internists, 9 family practitioners, and 3 psychiatrists. Minimum exclusion criteria were used with respect to concurrent medical ailments, age, and concomitant medications. Of the 380 patients admitted to the study, 325 were included in efficacy analyses, and 359 provided data for safety analyses. The average patient was a 51-year-old married white woman with a high school education and a skilled job. Bupropion administered in doses of 150-450 mg/day was highly effective in reducing depressive symptomatology as evaluated by the Hamilton Depression and Clinical Global Impressions scales, and the Zung Self-Rating Scale. No clinically significant bupropion-related changes in blood pressure, pulse rates, respiration rate, body temperature, or laboratory parameters were recorded; only 41 patients were discontinued due to intolerance to adverse experiences. There was a notable absence of daytime sedation, and of anticholinergic and cardiovascular side effects.

Effects of adenosine monophosphate on the reactivation of latent herpes simplex virus type 1 infections of mice.

Adenosine monophosphate pretreatment of mice with latent herpes simplex virus type 1 infections significantly reduced the rate of reactivation of latent virus. Adenosine monophosphate pretreatment did not, however, eradicate latent virus.

Concomitant development of [3H]-dopamine and [3H]-5-hydroxytryptamine uptake systems in rat brain regions.

1 Synaptosomal uptake mechanisms of 5-hydroxytryptamine and dopamine were examined in cerebral cortex, corpus striatum and midbrain plus brainstem of developing rats. 2 In all regions, there was generally a parallel biphasic development of both uptake systems; the most rapid increases occurred in the first two weeks postpartum, followed by a slower rate of increase. 3 Kinetic studies with dopamine indicated that the maturation involved increases in maximal uptake without a change in the substrate Km, suggesting that there is a change in the number or terminals but not in the uptake system per se.

Dopamine beta-hydroxylase distribution in density gradients: physiological and artefactual implications.

Knowledge of the vesicular origin of circulating dopamine beta-hydroxylase (DbetaH) is indispensable for any attempts to explain the parallelism or lack of it between circulating enzyme and catecholamines as they may relate to physiological stress, forms of hypertension, neurological disorders, and the response to pharmacological agents. The present study represents an effort to evaluate and to place in proper perspective data based on the DbetaH activity found in the region of the light vesicle peak of noradrenaline (NA), which is used as a quantitative measure of a population of small terminal vesicles. Distributions of vesicles and subvesicular components are compared with DbetaH and NA in sucrose-D2O density gradients used to prepare relatively pure fractions of large dense cored vesicles (LDV) from bovine splenic nerve. Although NA in sedimentable particles of the light vesicle peak is likely to be a valid measure of a small vesicle population, the following is demonstrated: (1) A substantial fraction (25%-37%) of the total sedimentable DbetaH activity can be proven to distribute in the region of the light vesicle peak from a tissue with an insignificant small vesicle population. Based on studies of vesicles from sequential nerve segments, this enzyme activity probably corresponds to a population of "immature" LDV which are undergoing axoplasmic transport and have not synthesized their full complement of transmitter. (2) Physical lysis which depletes the matrix of LDV causes redistribution of DbetaH activity from the heavy vesicle peak into the region of the light vesicle peak. Analogously, DbetaH associated with exocytosed LDV and retrograde transport particles is also likely to contaminate the region of the light vesicle peak. (3) Based on available data, it can be calculated that each small dense cored vesicle could contain only 0.1-0.5 molecules of DbetaH and that a contamination of only 0.016% LDV can account for all of the DbetaH reported to occur in the light vesicle peak of normal rat vas deferens preparations.

Ontogeny of (--)-[3H]norepinephrine uptake properties of synaptic storage vesicles of rat brain.

The ontogeny of[3H]norepinephrine uptake mechanisms has been examined in synaptosomes and storage vesicles isolated from rat whole brain. The [3H]norepinephrine accumulated by synaptosomes was low in neonates, but reached adult levels by 15 days of age. In contrast, development of[3H]norepinephrine uptake into isolated rat brain storage vesicles was not complete until 38 days of age. Kinetic analysis of the developing vesicular uptake mechanism revealed no change in Km, while maximal uptake increased progressively from birth to maturity. Storage vesicles from immature and adult rats exhibited similar energy requirements for uptake as determined by their dependence on ATP-Mg2+ concentration; furthermore, the degree of inhibition of [3H]norepinephrine uptake by other amines was the same in both vesicle preparations. Thus, storage vesicles isolated from adult and developing rats display an in vitro[3H]norepinephrine uptake mechanism with properties that are kinetically and pharmacologically similar. The results suggest that, while the number of storage vesicles in the central nervous system increases during development, those vesicles that are present possess a fully functional amine uptake system.